Several companies release recent news related to tackling some of the toughest cancers

By Jeffrey Bouley

For this installment of our Cancer Research News feature section, we thought we’d focus primarily on what’s happening lately with research and potential treatment for some of the most deadly and difficult-to-treat cancers around. And to start with, we will begin on a generally familiar and well-trod ground—breast cancer—but with an eye toward the very challenging subset of triple-negative breast cancer (TNBC).

In that vein, fall brought news from Bothell, Wash.-based Seattle Genetics Inc. of two clinical collaboration agreements for the evaluation of SGN-LIV1A in patients with TNBC. The potential therapeutic is an investigational antibody-drug conjugate (ADC) that targets the cell surface protein LIV-1. This protein is expressed on multiple solid tumor types, including breast, prostate, melanoma, ovarian and cervical.

The ADC will be tested in combination with Keytruda (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co. (known as MSD outside the United States and Canada), in a Phase 1b/2 clinical trial as a first-line treatment for locally advanced and metastatic TNBC. SGN-LIV1A in combination with standard chemotherapy will also be evaluated as neoadjuvant treatment in the Phase 2 I-SPY 2 TRIAL for newly diagnosed stage 2 or 3 human epidermal growth factor receptor 2 (HER2)-negative breast cancer, sponsored by Quantum Leap Health Care Collaborative. This cancer subgroup accounts for up to 85 percent of breast cancer and includes TNBC.

“Our new collaborations expand the clinical investigation of SGN-LIV1A by evaluating this ADC in earlier lines of treatment for TNBC, including the frontline setting in combination with pembrolizumab. In the neoadjuvant setting, SGN-LIV1A has the potential to benefit a broader population of women with breast cancer,” said Dr. Jonathan Drachman, chief medical officer and executive vice president of research and development at Seattle Genetics. “Breast cancer is the most common cancer in women, excluding some forms of skin cancer, in the United States. Of the over 250,000 new cases expected to be diagnosed in the US this year, about 15 to 20 percent are TNBC, which is very aggressive and associated with poor patient outcomes. With four clinical studies underway or planned for SGN-LIV1A in TNBC, we are advancing our goal to improve the health of women with this devastating disease.”

Four clinical studies are underway or planned for SGN-LIV1A in breast cancer, with a focus on TNBC. In addition to the aforementioned trials, SGN-LIV1A monotherapy is being evaluated in an ongoing Phase 1 trial for patients with metastatic breast cancer, including patients heavily pretreated for TNBC. A Phase 1b/2 trial is planned to evaluate SGN-LIV1A as part of a combination regimen as a second-line treatment for patients with metastatic TNBC who have not been previously treated with immunotherapy.

Moving to a less-talked about but very deadly cancer, Oslo, Norway-based Targovax ASA, a clinical-stage company focused on developing immuno-oncology therapies to target solid tumors, recently announced one-year data on survival rate, immune activation and safety in the modified cohort of the TG01 trial in resected pancreatic cancer patients

The trial is an open-label, Phase 1/2 trial of TG01/GM-CSF in combination with gemcitabine as adjuvant therapy for treating patients with resected adenocarcinoma of the pancreas. The trial consists of two cohorts: the main cohort of 19 patients and a second, modified cohort of 13 patients. The purpose of the modified cohort is to build on the positive findings from the main cohort in order to further optimize the TG01 treatment regimen and safety profile of the combination therapy. Although manageable, some allergic reactions were seen in patients in the main cohort when treating with TG01 and gemcitabine in parallel. Hence, the modified cohort received fewer TG01 injections overall than the main cohort, administered non-concomitantly with gemcitabine.

The modified cohort started recruitment in 2015, and the last patient enrolled has now been in the trial for one year. The one-year survival rate and safety data in the modified cohort showed that:

No serious adverse events related to allergic reactions have been reported.

“We are delighted that we maintain a strong immune response and one-year survival rate with the reduced dosing regimen, essentially equivalent to and consistent with the previously reported data from the main cohort,” said Dr. Magnus Jäderberg, chief medical officer of Targovax. “This further strengthens the safety profile of TG01 and adds valuable understanding that will help us optimize the dosing regimen in resected pancreatic cancer patients, a condition which is notoriously difficult to treat. We look forward to see the two-year survival data for the modified cohort next year.”

Meanwhile, moving up the torso to an area perhaps as familiar as breast cancer, we come to news of a new lung cancer study utilizing Inivata’s InVision liquid biopsy platform, led by the Addario Lung Cancer Medical Research Institute (ALCMI), a patient-founded not-for-profit global research consortium.

We talk about the study more in detail in the Diagnostics section of this issue, on page 31 in the article “Lung cancer not just smokers’ disease,” but in a nutshell, the goal of the study is to use InVision analysis to determine the potential role for circulating tumor DNA (ctDNA) in measuring minimal residual disease in patients following surgical resection in non-small cell lung cancer (NSCLC) with a view to help identify those patients who are in need of further therapy, and also to explore the value of ctDNA in monitoring for relapse.

The study’s primary objective is to correlate the presence of ctDNA following surgical resection with disease recurrence in NSCLC. Additional objectives include exploring the role of ctDNA in the ongoing monitoring of patients during and after therapies administered following surgery with a view to improving long-term outcomes.

Also in the realm of diagnostics and NSCLC, interim analysis of the INSIGHT study examining the impact of VeriStrat testing on treatment decisions in patients with NSCLC reportedly shows that VeriStrat testing can impact treatment planning for patients with early-stage disease as well as more advanced disease.

INSIGHT is a national, multi-institutional prospective observational trial of patients with NSCLC for whom physicians ordered VeriStrat testing. The primary endpoint of the study is observing the impact of VeriStrat on treatment planning. An interim analysis of 714 patients enrolled between May 2016 and June 2017 was conducted on the primary study endpoint. The analysis focused on the 170-patient subset with stage IA-IIIA disease at the time of study entry.

The interim analysis showed that patients who tested VeriStrat-Good (VS-Good) were treated significantly differently than patients who tested VeriStrat-Poor (VS-Poor), receiving non-systemic treatments such as radiation therapy (11 percent), surgery (12 percent) or observation (11 percent). Patients who tested VS-Poor did not receive these treatments. Nearly all patients with a VS-Poor test result received systemic therapies (97 percent), compared to 66 percent of the VS-Good patients. In contrast, per multivariate analysis, treatment decisions were not impacted by other prognostic factors (performance status, histology and age).

Continuing the theme of NSCLC but with a more regulatory twist as well as a trial one, Checkpoint Therapeutics Inc., a Fortress Biotech company, recently announced that the U.S. Food and Drug Administration (FDA) had granted Orphan Drug designation to CK-101 (also known as RX518), the company’s third-generation epidermal growth-factor receptor (EGFR) inhibitor, for the treatment of EGFR mutation-positive NSCLC.

CK-101 is currently being studied in the Phase 1 dose-escalation portion of a Phase 1/2 clinical study. The Phase 1 portion of the study is evaluating the safety and tolerability of ascending doses of CK‐101 in patients with advanced solid tumors to determine the maximum tolerated dose and/or recommended dose for the Phase 2 portion of the study. The Phase 2 portion will evaluate the safety and efficacy of CK-101 in patients with EGFR T790M mutation-positive NSCLC.

“Securing Orphan Drug designation is a significant milestone that will support the clinical development of our lead targeted therapy, CK-101, in EGFR mutation-positive NSCLC,” said James F. Oliviero, president and CEO of Checkpoint. “This Orphan Drug designation builds upon the issued U.S. composition of matter patent for CK-101, and could provide the benefit of additional market exclusivity.”

Meanwhile, for a very deadly type of cancer we hear even less of than pancreatic cancer, PCI Biotech recently gained Orphan Drug designation from the FDA for Fimaporfin, a drug aimed toward treating patients suffering from cholangiocarcinoma (bile duct cancer).

And finally, Agilent Technologies Inc. recently announced its Dako PD-L1 IHC 22C3 pharmDx assay has an expanded label approved by the FDA for use as an aid in identifying gastric or gastroesophageal junction (GEJ) adenocarcinoma patients for treatment with Keytruda. The FDA also announced on Sept. 22 that Keytruda is now approved for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma. These tumors express PD-L1 as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy.

The expanded approvals for PD-L1 IHC 22C3 pharmDx and Keytruda means that these patients now have the possibility of receiving a targeted anti-PD-L1 immunotherapy.

Gastric cancer is the fifth most common malignancy worldwide and the third most common cause of cancer death. The prognosis for patients diagnosed with advanced stage IV gastric cancer is poor, with only a 4-percent five-year observed survival rate. Previously, gastric or GEJ adenocarcinoma patients had few therapeutic options, and those available included highly toxic chemotherapy.

“We are pleased that the U.S. FDA approved the expansion of use for PD-L1 IHC 22C3 pharmDx assay, as it gives patients with gastric or GEJ cancer the possibility of having their tumor sample tested for PD-L1 expression and determining eligibility for treatment with Keytruda.” said Jacob Thaysen, president of Agilent’s Diagnostics and Genomics Group.

PD-L1 IHC 22C3 pharmDx was used to assess PD-L1 expression in patients treated with Keytruda in the KEYNOTE-059 trial. KEYNOTE-059 is a registrational, Phase 2, global, multicenter, non-randomized, open-label multicohort trial investigating the use of Keytruda in patients with advanced gastric or GEJ adenocarcinoma.

Bio-Techne awards research grant to immuno-oncology researcher

MINNEAPOLIS—Advanced Cell Diagnostics (ACD), a Bio-Techne brand, recently announced the winner of its “RNAscope ISH Get Hybridized” giveaway, designed to recognize and support groundbreaking research with RNAscope in-situ hybridization (ISH) technology. The winner, Dr. Andreas Behren, Group Leader in Cancer Immunobiology at the Olivia Newton-John Cancer Research Institute in Melbourne, Australia, received the grand prize—a $40,000 research grant—at a reception at Madame Tussauds in Washington, D.C., on Nov. 13.

Several thousand researchers from around the world participated in the yearlong giveaway by describing their research and its impact, as well as a potential role for RNAscope ISH. In addition to the grand prize, ACD also gave away eight $2,000 grants during the year. Behren was awarded the grand prize in recognition of his research on the interplay between the immune system and cancer—classifying immune cells and studying their activation status.

Describing the impact of his research, Behren commented: “The information from our research could be a step forward in understanding why some tumors respond to immunotherapy and others don’t. When I heard I’d won the giveaway, I immediately thought about the possibilities for RNAscope in our projects. Often there isn’t money to develop or adjust novel assays or methods to specific questions, so I am delighted and grateful to now have this opportunity with the ACD research grant.”

Behren went on to explain the utility of RNAscope in his research: “Using RNAscope, we hope to track and visualize antigen-specific T cells in situ and profile their activation status and immune-checkpoint expression pattern. With this information, it would be possible to determine the activation profile of tumor-specific T cells and their location within the tumor microenvironment in FFPE tissues. Hopefully, this will reveal novel targetable mechanisms that contribute to resistance to immunotherapies.”

ACD’s RNAscope and BaseScope ISH assays provide a platform capable of detecting and quantifying RNA at single‐molecule sensitivity. As Xiao-Jun Ma, chief scientific officer at ACD, noted: “RNAscope is on its way to becoming a gold standard for in-situ expression analysis, thanks to its wide-ranging utility in many research areas. Dr. Behren’s work on the functional characterization of immune cells in the native tumor microenvironment is a great example of groundbreaking research facilitated by the unique advantages of RNAscope. I am confident that RNAscope will prove instrumental in the results of this ongoing work and in advancing this exciting field. We look forward to continue working with this group as they push the limits of our technology.”

Compugen teams with Mount Sinai on myeloid immuno-oncology targets

HOLON, Israel—Compugen Ltd., a leader in predictive discovery and development of first-in-class therapeutics for cancer immunotherapy, has entered into a multiyear cancer immunotherapy research collaboration with the Icahn School of Medicine at Mount Sinai in New York, under the direction of Dr. Miriam Merad, director of the Precision Immunology Institute and co-leader of the Cancer Immunology program at Mount Sinai. Merad is a leader in the field of myeloid biology for the development of novel cancer immunotherapies and is a member of Compugen’s scientific advisory board (SAB).

Noted Merad: “After joining Compugen’s SAB earlier this year, I grew more familiar with and impressed by the company’s promising novel immuno-oncology drug target pipeline. I am looking forward to collaborating with Compugen scientists in advancing the company’s myeloid target candidates portfolio. Targeting myeloid biology, through Compugen myeloid target candidates, may potentially elicit a strong antitumor effect. Therapeutic development against myeloid targets can potentially provide a solution for cancer patients non-responsive to current treatments or serve as a combination therapy with existing immune checkpoint inhibitors in order to increase their response rate.”

“Following our fruitful multi-year collaboration with Johns Hopkins University School of Medicine, we are pleased to announce yet another research collaboration with a leading academic institution led by a world-renowned expert in her field in order to further understand and advance our novel immuno-oncology targets towards clinical trials,” said Dr. Anat Cohen-Dayag, president and CEO of Compugen. “We look forward to collaborating with Dr. Merad and her team and believe that this partnership will potentially broaden our pipeline and provide new treatment options for patients whose disease is refractory to existing immune checkpoint inhibitors or other treatment modalities.”

The collaboration will focus on the research and target validation of selected myeloid candidates discovered by Compugen for their potential to serve as a basis for cancer immunotherapy treatments, including the validation of their role in innate immunity and involvement in tumor biology.

Salk researchers get $2.5M for pancreatic cancer trial

LA JOLLA, CAlif.—Salk Institute professor and Howard Hughes Medical Institute investigator Dr. Ronald Evans has been awarded $2.5 million by Stand Up To Cancer (SU2C) as part of a multi-institution team to conduct clinical studies to open up a new avenue for immunotherapy in the treatment of pancreatic cancer. While the cancer normally excludes immune T cells, the Evans lab discovered that modified vitamin D reprograms the cancer environment in a way that may allow the Merck & Co. drug Keytruda to invade and destroy the tumor.

The award, spread out over three years, is part of SU2C Catalyst, which uses “funding and materials from the pharmaceutical, biotechnology, diagnostic and medical devices industries to accelerate research on cancer prevention, detection and treatment,” according to SU2C. This SU2C award is supported by the U.S.-based pharmaceutical company Merck (known as MSD outside the United States and Canada), which is providing funding and the immunotherapy drug Keytruda (pembrolizumab) for the clinical trial.

“The Evans lab’s discovery that vitamin D can make pancreatic tumors more susceptible to drug therapy suggested the added potential to also wake up the patient’s own immune system.” says Salk President Elizabeth Blackburn. “Combining vitamin D and immuno-oncology gives new hope to tens of thousands of pancreatic cancer patients whose treatment options have been devastatingly limited thus far. This could be a game changer.”

Pancreatic cancer is one of the deadliest types of cancers, both because it is often diagnosed late and because its unique tumor environment makes it impervious to both chemotherapy and immunotherapy, Salk points out. Pancreatic tumors co-opt the body’s natural wound-healing response, hiding behind a wall of immune cells and inflammatory molecules almost like an armor that drugs can’t penetrate. In the meantime, the tumor uses the nutrients that should be supporting the immune cells to nourish itself.

“We have to bring pancreatic cancer treatment into the modern age,” stressed Evans, who is the director of Salk’s Gene Expression Laboratory and holder of Salk’s March of Dimes Chair in Molecular and Developmental Biology. “This cancer is a particularly strong foe. It has resisted basically everything thrown at it. But we believe that it can be tamed, conquered and hopefully cured. This grant is a big step toward making that happen.”

As Salk notes, the “armor” surrounding and protecting pancreatic tumors is controlled by a molecular switch that the Evans lab showed can be controlled by a special synthetic form of vitamin D. When Evans and colleagues administered the drug to mice and a small number of humans, it “cooled down” the inflamed environment, allowing chemotherapy to be more effective.

“The Salk team will work with Translational Genomics Research Institute (TGen) in analyzing patient samples to figure out whether our theories about combining vitamin D and immunotherapy are correct or not–and we’ll know that pretty rapidly,” said Dr. Michael Downes, a Salk senior scientist and co-principal investigator of the new grant.

Heading the clinical group in Arizona is Dr. Daniel Von Hoff of TGen, who also is the chief scientific officer at HonorHealth, a primary clinical trial site. Salk will also work closely with Dr. Andrew Lowy and the clinical oncology group at the University of California, San Diego Cancer Center.

“We are extremely excited about this trial, because for the first time we’re able to get patients into remission—even stage IV patients—where we see the tumor shrink,” noted Von Hoff. “The high dose of this vitamin D derivative allows the body’s immune system to go from viewing the cancerous cells from something that is normal, to recognizing them for the invaders they are and hopefully attacking them as they would a common infection.”

Investigating microbiome therapeutics for immuno-oncology

CAMBRIDGE, Mass.—Seres Therapeutics Inc., The University of Texas MD Anderson Cancer Center and the Parker Institute for Cancer Immunotherapy in mid-November announced a collaboration to evaluate the potential of Seres’ microbiome therapies to improve the outcomes of cancer patients treated with currently-available immunotherapy.

The collaborators plan to initiate a randomized, placebo-controlled clinical study at MD Anderson, sponsored by the Parker Institute, in patients with advanced metastatic melanoma. The clinical trial will evaluate the impact of an anti-PD-1 checkpoint inhibitor with adjunctive microbiome therapy on patient outcomes. Seres is developing SER-401, a preclinical stage oral microbiome therapy comprising a rationally-designed consortium of live bacteria, to improve the efficacy and safety of immunotherapy.

Published studies provide preclinical and clinical evidence demonstrating that the composition of bacteria in the gastrointestinal microbiome may impact response to checkpoint inhibitor therapy. On Nov. 2, 2017, Science published research by Dr. Jennifer Wargo and colleagues from MD Anderson indicating that the composition of the gut microbiome may influence checkpoint inhibitor response in melanoma patients. This research also demonstrated that the favorable microbiome properties found in checkpoint inhibitor responder patients are able to be transferred to mice. The results provide support for the clinical study of microbiome therapeutics to augment the clinical benefit of cancer immunotherapy.

Seres also received an exclusive option, with pre-defined financial terms, to license intellectual property rights from MD Anderson related to the use of bacteria in combination with checkpoint inhibitors.

“MD Anderson, and in particular Dr. Wargo’s laboratory, is leading the charge to better understand the microbiome and the response to immune checkpoint inhibitors,” said Dr. Roger J. Pomerantz, president, CEO and chairman of Seres. “We look forward to combining our insights and capabilities with both MD Anderson and the Parker Institute to advance microbiome therapies to augment immunotherapy in cancer patients toward the clinic, with the ultimate goal of improving outcomes for patients facing life-threatening tumors with significant unmet medical need.”

“Immunotherapy has represented an important advance for melanoma and other cancers. However, in the majority of patients, the response is not adequate to durably control disease,” noted Wargo, who is associate professor of genomic medicine and surgical oncology at MD Anderson. “Modulation of the microbiome is a promising approach that may improve the therapeutic benefit of checkpoint therapy.”

UTM and Medicxi launch Janpix

CAMBRIDGE, Mass & MISSISSAUGA, Ontario—Janpix Inc., a privately held biopharmaceutical company dedicated to the discovery and development of inhibitors targeted to signal transducer and activator of transcription (STAT) proteins, announced that it has closed a $22-million (Canadian dollars) investment round led by Medicxi, a GlaxoSmithKline- and Johnson & Johnson-backed venture fund, that initially seeded the company. The company is advancing selective, small molecule inhibitors of STAT proteins, originally discovered at the University of Toronto Mississauga (UTM) by Prof. Patrick Gunning, towards clinical development.

Until now, though, STAT proteins remained a hard-to-crack molecular target as intracellular protein-protein interactions are notoriously difficult to inhibit with small molecules. Previous efforts in this field have often resulted in either non-selective compounds or compounds binding to upstream targets. Using technologies and new chemistry developed by Gunning, Janpix is now advancing highly potent and selective STAT3 and STAT5 inhibitors, as well as pan-STAT3/5 inhibitors. With selective compounds in hand, the hope is that these targets can now be further investigated in the clinic.

STAT proteins, in particular STAT3 and STAT5, play a key role in regulating cell cycle, apoptosis and proliferation, and it is widely recognized that their activity is implicated in a number of solid and hematological cancers. More recent research suggests that inhibition of STAT proteins also has a profound impact on the tumour microenvironment, which offers the potential for these inhibitors to have a dual impact on tumors.